Dextrorotatory 3r-n-monomethyl-amino-4c-phenyl-4t-ethoxycarbonicyclohexene-1 and process for the production thereof

ABSTRACT

The present invention relates to (+)-3r-N-monomethylamino-4cphenyl-4t-ethoxycarbonylcyclohexane-1 ((+)-I),   salts thereof, and methods for the production of said compounds. The compounds of the invention exhibit analgesic activity in mammals and are useful for the reduction or alleviation of pain.

United States Patent [1 1 Satzinger et al.

May 6, 1975 DEXTROROTATORY 3r-N-MONOMETHYL-AMINO-4c-PHENYL-4t-ETHOXYCARBONlCYCLOHEXENE-l AND PROCESS FOR THE PRODUCTION THEREOF[75] Inventors: Gerhard Satzinger; Wolfgang Herrmann, both ofDenzlingen; Manfred Herrmann, Gundelfingen, all of Germany [73]Assignee: Warner-Lambert Company, Morris Plains, NJ.

[22] Filed: July 5, 1973 [21] Appl. No.: 376,845

Related U.S. Application Data [63] Continuation-impart of Ser. No.266,036, June 26,

1972, abandoned.

[52] U.S. Cl 260/471 A [5|] Int. Cl. ..C07c 101/14 [58] Field of Search260/47l A [56] References Cited UNITED STATES PATENTS 3,679,732 7/1972Novack 260/471 A Primary Examiner-Lorraine A. Weinberger AssistantExaminer-L. A. Thaxton Attorney, Agent, or FirmAlbert H4 Graddis; FrankS. Chow; George M, Yahwak [57] ABSTRACT The present invention relates to(+)-3r-N- monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexane-l saltsthereof, and methods for the production of said compounds. The compoundsof the invention exhibit analgesic activity in mammals and are usefulfor the reduction or alleviation of pain.

6 Claims, No Drawings DEXTROROTATORY 3R-N-MONOMETHYL-AMlNO-4C-PHENYL-4T-ETHOXYCARBONICYCLOHEXENE-l AND PROCESS FOR THE PRODUCTION THEREOF Thisapplication is a continuation-in-part of our copending application, U.S.Ser. No. 266,036 filed June 26, I972, now abandoned.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to(+)-3r-N- monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-l, thehydrochloride, the D*(-)0,0- dibenzoyltartrate, theL-(+)-0,0-dibenzoyltartrate and other medicinally acceptable acidaddition salts thereof. The present invention also relates to twomethods for the production of the afore-named optically active base of(+)-3r-N-monomethylamino-4c-pheny]-4tethoxycarbonylcyclohexene-l andsalts thereof. The first rncthod involves the resolution of (i)'3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-l into itsoptical antipodes. The alternative method consists of thebrominative-hydrolytic demethylation of(+)-3r-N-dimethylamino-4c-phenyl-4tethoxycarbonylcyclohexene-l to(+)-3r-N- monomethylamino-4c-phenyL4t-ethoxycarbonylcyclohexene- 1.

The compounds of this invention, (+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-l and saltsthereof, show analgesic activity in mammals and are more potent and havea higher therapeutic ratio than the corresponding racemic compound,(i)-3r-N-monomethylamino-4c-phenyl-4tethoxycarbonylcyclohexene-1.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to(+)-3r-N- monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-l, thehydrochloride, the D-()-0,0- dibenzoyltartrate, theL-(+)-0,0-dibenzoyltartrate and other medicinally acceptable acidaddition salts thereof. This invention also relates to methods for theproduction of (+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-l and the afore-named salts.

The parent compound of this invention, (+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexenel is thedextrorotatory isomer of the potent analgesic,(:)-3r-N-monomethylamino-4c-phenyI-4tethoxycarbonylcyclohexene-Idescribed in US. Pat. No. 3,792,080. The dextrorotatory base isstructurally related to the effective, relatively non-toxic analgesic,(i)-3r-N-dimethylamino-4c-phenyl-4tethoxycarbonylcyclohexene-l,disclosed in US. Pat. No. 3,557,127, issued Jan. 19, 1971; the formerbeing the nitrogen demethyl derivative of the latter.

The parent compound of this invention (+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-l, is prepared bytwo fundamentally different processes. In the first, racemic i.e.,(i)-3r-N- monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-l isdissolved in a suitable solvent, such as, methanol, ethanol, 2propanol,water or acetone, preferably acetone, and the resulting solution istreated with a solution of one molar-equivalent ofD-()-0,0-dibenzoyltartaric acid hydrate and a,suitable solvent, such asmethanol, ethanol, 2-propanol, water or acetone, preferably acetone, atroom temperature. The solution is allowed to stand at room tempera turefor approximately l8 hours and the precipitate, which consistspredominantly of (-)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-lD-()-0,0-dibenz0yltartrate, is removed by filtration.

The filtrate is evaporated, the residue is dissolved in an aqueoussystem and the base is liberated by the addi tion of an aqueous solutionof an alkaline metal hydroxide, for example, sodium hydroxide, potassiumhydrox' ide, or ammonium hydroxide. By this process, (+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-l is obtainedas a colorless oil.

Hydrohalides of the dextrorotatory base are prepared by treatment of asolution of (+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-l and anappropriate solvent, such as ethyl acetate, with a solution of thehydrogen halide and the same solvent. For example, the hydrochloride ofis obtained when an ethyl acetate solution of (+)-3r N-monomethylamino-4c-phenyl-4t-ethoxycarbonyicyclohexene-l hydrogenchloride is added to an ethyl acetate solution of(+)-3nN-monomethylamino-4cphenyl-4t-ethoxycarbonylcyclohexenel TheD-(-)-0,0-dibenzoyltartrate of (+)3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcy clohexene-l is obtained bytreatment of a solution of (+)-3r-N-monomethylamino-4c-phenyl-4tycarbonylcyclohexene-l and a suitable inert solvent, for exampleacetone, with a solution of -(*)-O,O-dibenzoyltartaric acid hydrate andan appropriate solvent, such as acetone. The diastereoisomeric salt,(+)-3r-N-monomethylaminc-4c-phenyl 4t-ethoxycarbonylcyclohexene-l Ldibenzoyltartrate, of (+)-I dibenzoyltartrate is obtained directly frommonomethylamino-4c-phenyl-4t-ethoxycarbonyIcyclohexene-l by the additionof a solution of L -l-Qodibenzoyltartaric acid hydrate and a suitablesolvent such as acetone to a solution omonomethylamino-4c-pheny]-4t-ethoxycarbonylcyclohexene-l and anappropriate solvent such as acetone.

The resolution of a racemic mixture of basic compounds into thecorresponding optical isomers usually involves the treatment of theracemic mixture with an optically active acid followed by fractionationof the resultant mixture into its optically pure components andsubsequent liberation of each optically pure bas from the correspondingdiastereoisomer. The fractionation step, usually repeatedrecrystallizations, of the common resolution process is time-consum1ng,expfin sive and wasteful in that very low yields of optically purecompounds are normally obtained.

Unlike the traditional resolution processes, the present processutilizes both the dextroand levorotatory isomers of the optically activeacid. In the instant case, ,O-dibenzoyltartaric acid hydrate and)-O,O-dibenzoyltartaric acid hydrate were employed and the discovery wasmade that the former forms a difficultly soluble salt in essentiallyquantitative yield With the levo rotatory base so that the desireddextrorotatory base can be recovered from the mother liquor. Thediscovery was also made that the latter forms a sparingly soluble saltwith dextrorotatory base so that it may be separated directly from thera c mixture in high yield. The present process represents an unexpectedand beneficial improvement over traditional resolution processes.

The instant resolution process is delineated below in schematic form:

ent of (+)ll is unexpected to one skilled in the art. Moreover, thedemethylation of (+)-ll to (+)-l without racemization of the susceptibleoptical centers is unpredictable to one so skilled.

(-1-) -I +D-%-) -C H O -H 0.--) (-)--I-D(043 1-1 mother liquor HCI. -Iincl 9* L- -C li 0 41 0 l 1s 14s' 2 0 I L (2 E 0 H20 I n c ii o In thesecond process,(+)-3r-dimethylamino-4cphenyl-4t-ethoxycarbonylcyclohexene-l, describedin West German Pat. No. 1,923,247, issued July 8, 1971, is converted to(+)-3r-monomethylaminotc-phenyl- 4t-ethoxyearbonylcyclohexene-l by theprocedure reported in US. Pat. Application, Ser. No. l17,l42, for thedemethylation of (i)-3r-dimethylamino-4c-phenyl-4tethoxyearbonylcyclohexene-l to(i)-3rmonomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-l. In theinstant process,(+)-3rdimethylamino-4cphenyl-4t-ethoxycarbonylcyclohexenel is dissolvedin a suitable solvent, such as chloroform, and is brominated by thedropwise addition of bromine dissolved in the same solvent at -lC to Cpreferably at -l0C, to said solution. The reaction mixture is thenhydrolyzed at room temperature and the desired dextrorotatory isomer of(+)-3r--N- monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-l isisolated as the hydrochloride by basification with an alkaline metalhydroxide, for example, sodium hydroxide, potassium hydroxide, orammonium hydroxide, separation of the organic phase, evaporation of theorganic phase, dissolution of the residue in an appropriate solvent suchas ethyl acetate and addition of hydrogen chloride in the same solvent.The present demethylation process is depicted below in schematic form:

The lowercase letters r, c and t preceding the name of a functionalgroup in the nomenclature of the instant cyclohexenes means reference,cis and trans, respectively, and defines the stereochemical arrangementof the groups attached to the cyclohexene ring system. As shown in thespatial structural formula for (+)-3r'N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene shown below, whenthe monomethylamino group is arbitrarily chosen as the reference groupand located above the average plane of the cyclohexene ring, the phenylgroup is situated on the same side of the average plane of thecyclohexene ring system as the monomethylamino group, i.e., is cis (c)to the reference (r) group, and the ethoxycarbonyl group is situated onthe opposite side of the average plane of the cy clohexene ring as thereference group, i.e., is trans (t) to the reference group.

The above described demcthylation process presents several unexpectedand unpredictable features. Prior to the disclosure US Pat. No.3,792,080, the fundamental transformation, the brominative-hydrolyticcleavage of one of the two methyl groups bound to the nitrogen atom of(+)-ll, of the above process was without precedent in organic chemistry.The high yield conversion of (+)-ll to (+)-l without concomitantbromination of the olefinic linkage, allylic positions or the phenylsubstitu- The compounds of the present invention exhibit analgesicactivity and are useful for the reduction of and alleviation ofpain.Like (i)-3r-N-monomethylamino-4cphenyl-4t-ethoxycarbonylcyclohexene-l tlscribed in US. Pat. No. 3,792,080, (+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene, thedextrorotatory optical isomer of (i)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarboylcyclohexene-l showsanalgesic activity in the phenyl-pquinone writhing test. The instantcompound (+)-3 r-N-monomethylamino-4c-pheny1-4t-ethoxycarbony1cyclohexene-l hydrochlorideis 3.3, 2.4 and 2.5 times more potent than(i)-3r-N-monomethylamino-4cphenyl-4t-ethoxycarbonylcyclohexene-1hydrochloride when administered intragastrically (ig), subcutaneously(sc) or intravenously (iv), respectively, to the mouse in this test. Inaddition, the dextrorotatory isomer(+)-3r-N-monomethylamino-4c-phenyl-4tethoxycarbonylcyclohexene-1hydrochloride is therapeutically more effective by a factor of 2.6 to3.1 (depending upon the mode of administration) than its racemiccounterpart.(i)-3r-N-monomethylamino-4cphenyl-4t-ethoxycarbonylcyclohexenelhydrochloride, as defined by the therapeutic ratio (Q). The D-(-)-0,0-dibenzoyland L-(+)-0,0-dibenzoyltartrates of(+)-3r-N-monomethylamino-4c-phenyl-4tethoxycarbonylcyclohexene-1 aremore potent and more effective analgesics than (t)-3r-N-monomethylamino-4c-pheny-4t-ethoxycarbonylcyclohexene-l hydrochloride inthe aforementioned tests and the optically active base (+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-l is about aspotent and effective as the racemic hydrochloride (iH-lCl. Moreover, thedextrorotatory base(+)-3r-N-monomethylamino-4c-phenyl-4tethoxycarbonylcyclohexene-1 as wellas the salts thereof exemplified in this specification are more potentand therapeutically effective than Merperidine, the present leader inthe analgesic market. The optically active compounds of this inventionshow unexpected and beneficial biological properties over the prior artracemic compound (i)-3r'N-monomethylamino-4c-pheny1-4t-ethoxycarbonylcyclohexene-l and theclinically useful analgesic, Merperidine.

Therapeutic ratio (0) is defined as the ratio of lethal dose-S0 (LDdivided by the effective dose-50 (ED that is,

The biological data is displayed in tabular form in the chart shownbelow:

The compounds of this invention can be formulated with variouspharmaceutical carriers to form dosage units for administration tomammalian hosts. These dosage forms, which are well known to thoseskilled in the art, include tablets, capsules, solutions, suspensions,emulsions, syrups, etc. for oral administration, suppositories forrectal administration and solutions and other liquid compositions forparenteral administration. Pharmaceutical carriers, also apparent topersons skilled in the art, include inert substances such as water,saline, gelatin, lactose, starch or other compatible materials commonlyused for the formulation of medicaments. The dosage forms can besterilized, buffered, preserved, etc. Wetting agents, osmotic pressuremodifiers, such as salts, emulsion stabilizers, etc., can be included inthe formulation. The compositions can be formulated by conventionalmethods and techniques known to those skilled in the art.

Formulations containing approximately 5 to 30 mg of the analgesiccompounds of this invention can be administered three times a day tohuman subjects.

The following examples serve to illustrate the embodiments of theinvention and are not to be inter preted as limiting the scope of theinvention:

EXAMPLE l (+)-3r-N-MONOMETHYLAMlNO-4c-PHENYL-4t-ETHOXYCARBONYLCYCLOHEXENE-1 RESO- LUTION METHOD.

In this example, a solution of 259.4 g 1 mole) of (i)-3rN-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-l and acetone(0.5 l.) is added at room temperature to a solution of 376.3 g (1 mole)of D-(- )-0,0-dibenzoy1tartaric acid-monohydrate in 1.5 l. of acetone.After standing overnight, the precipitate is collected. It consistsmainly of ()-3r-N-monomethylamino-4c-phenyl-4tethoxycarbonylcyc1ohexene-( 1 )D-(-)-0,0-dibenzoyltartrate. The filtrate is evaporated to dryness. Thecrystalline residue is dissolved in water, the base is liberated byammonium hydroxide and extracted with benzene. After drying the organicphase over anhydrous sodium sulfate, the solvent is evaporated. A resi-CHART Type of LI) Acute Toxicity Mouse ED Phenyl-p-quinone MouseAdminimg/kg Confidence Limits mg/kg Confidence Limits TherapeuticSubstance stration Ratio Lower Upper Lower Upper Q DL.1-IC1 ig. 206.8172.3 248.2 20.0 17.0 23.6 10.3 sc. 184.9 146.7 233.0 4.2 3.3 5.2 44.0iv. 40.5 33.7 48.5 3.6 3.0 4.3 11.2 D.HC] ig. 191.9 136.1 270.6 6.0 4.77.7 32.0 sc. 204.2 185.6 224.6 1.77 1.14 2.73 115.3 iv. 50.0 48.8 56.91.45 1.04 2.87 34.4 D. D.Dibenzoylig. 634.9 511.1 917.7 17.8 13.1 24.238.4

D-tartrate D.Dibenzoy1- ig 1616.7 1325.2 1972.4 26.6 22.1 31.9 60.7

L-tartrate D (b ig. 241.0 181.2 320.5 22.5 17.3 29.2 10.7 Me eridine ig.252.0 205.7 308.7 62.2 48.9 78.9 4.05

5c 154.0 122.0 194.3 16.6 13.1 20.9 9.3 iv. 49.4 42.4 57.5 5.5 3.74 8.088.9

* Meperidinc Pcthidine Dolantin due of 104 g of(+)-3r-N-monomethylamino-4cphenyl-4t-ethoxycarbonylcyclohexene-( l) isobtained as a colorless oil, [01],; +355 (5 g/l ml methanol).

To obtain (+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-l hydrochloride, 100 g (0.385 mole) of the(+)-base obtained above are dissolved in 400 ml of anhydrous ethylacetate and, with stirring at room temperature, a solution of 14 g(0.385 mole) of hydrogen chloride in 400 ml of ethyl acetate is addeddropwise. After cooling, the precipitate is collected and washed withethyl acetate; yield: 97 g (85 percent of theory) of(+)-3r-N-monomethylamino-4cphenyl-4t-ethoxycarbonylcyclohexene-( 1hydrochloride as colorless crystals, m.p. 210-2l2C; [01],, +315 (10g/IOO ml of water).

To a solution of 26 g (0.1 mole) of (+)-3r-N-monomethylamino4c-phenyl-4t-ethoxy-carbonylcyclohexene-( l and 100 ml ofacetone was added a solution of 37.6 g (0.1 mole) ofD-()-0,0-dibenzoyltartaric acid monohydrate and 100 ml of acetone. Theformed precipitate is collected. The yield is 20.2 g of salt, [Q1 +78(10g/lOO ml methanol). The salt is recrystallized twice from a small amountof methanol. The yield then amounts to 8.5 g of (+)-3r-N-monomethylamino-4c-phenyl-4tethoxycarbonylcyclohexene-( l )D-(-)-0,0-dibenzoyltartrate as colorless crystals, m.p. 113 C, [(11 +865 (1O g/IOOml methanol).

To a solution of 26 g (0.1 mole) of (+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-( 1 and 50 ml ofacetone is added a solution of 37.6 g (0.1 mole) ofL(+)-0,0-dibenzoyltartaric acid monohydrate and 150 ml of acetone atroom temperature. After standing overnight, the precipitate wascollected and washed with a small amount of acetone. The crude yield is32.3 g, m.p. 175-6C, [+1 +208.5 (2 g/ 100 ml methanol). The salt isrecrystallized from 500 ml of methanol to give 22 g of(+)-3rmonornethylamino-4c-phenyl-4tethoxycarbonylcyclohexene-( l)L(+)-0,0-dibenzoyl tartrate, m.p. 1856C, [011 +220 (2 g/lOO mlmethanol).

EXAMPLE 2 (+)-3r-N-MONOMETl-IYLAMINO-4c-PI-IENYL-4t-ETHOXYCARBONYLCYCLOHEXENE- l DE- METI-IYLATION METHOD.

To a solution of 273.4 g (1 mole) of(+)-3rdimethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-( l) and 500ml of chloroform, cooled to 10 C, a solution of 159.8 g (1 mole) ofbromine and 150 ml of chloroform is added dropwise over 1.5 hours, withstirring. After the addition is complete, the reaction mixture isstirred at -10 C for 30 minutes. The orangecolored reaction solution ispoured into 4.1 of water and the mixture is stirred for about 5 hours atroom temperature until it is almost colorless. The product is madealkaline with ammonium hydroxide, the organic phase is washed twice withwater and dried over magnesium sulfate, and the solvent is evaporated. Aresidue of 260 g is obtained. The residue is dissolved in 1 l. ofanhydrous ethyl acetate and a solution of 36.5 g (1 mole) of hydrogenchloride and l 1. of ethyl acetate is added slowly. The resultantprecipitate is collected, washed and dried; yield: 186 g (63 percent oftheory) f(+)-3r-N-monomethylaminoic-phenyl-4tethoxycarbonylcyclohexene-( l)hydrochloride, as colorless crystals from ethyl acetate, m.p. 2lO-211C,[01],, +320 g/100 ml of water).

EXAMPLE 3 ACUTE TOXICITY EVALUATION The test group consisted of 6 malemice (NMRI), each mouse weighing between 20 and 27 g. The animals werefasted (water was available ad libitum) for 16 to 18 hours prior toadministration of the test substance. A solution of the test substance,2 ml/ g of body weight in the case of intragastric administration and 1ml/ 100 g of body weight in the case of intravenous and subcutaneousadministration, was given to each animal and the dose was then increasedby a factor of 1.3 for each subsequent administration. The animals wereobserved for 7 days. The test results were evaluated according to thestatistical method of J. T. Litchfield, Jr. and F. Wilcoxon, Journal ofPharmacology and Exaperimental Therapeutics, 96, 99 (1949). The resultsof the statistical analysis are presented in the Chart.

EXAMPLE 4 ANALGESIC ACTIVITY EVALUATION PHE- NYL-p-QUINONE WRITHING TESTThe test group consisted of 12 male mice (NMRI), each mouse weighingbetween 20 and 27 g. The test compound was given to each animalintragastrically or subcutaneously, and after 15 and 30 minutes, a 0.02percent solution of phenyl-p-quinone was administered intraperitoneallyat a dose of 1.25 ml/lOO g of body weight. When the test substance wasadministered in travenously, the solution of phenyl-p-quinone was givenimmediately thereafter. The animals were observed for 20 minutes andthose animals which did not show typical pain reaction were consideredto be protected. The results of a given test group were discarded ifless than 11 out of 12 animals of the corresponding control groupresponded to the chemical insult.

These test results were also evaluated according to the statisticalmethod of Litchfield and Wilcoxon.

Having described out invention, What we desire to secure by LettersPatent is:

1. A compound of formula (+)-lmonomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-l of formula(+)-l which comprises treatment of (+)-3r-N-dimethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-l of formula (+)-I]with bromine in chloroform at 1 5 to 0C. followed by treatment of thebrominated product with water and recovery of by basification,extraction and evaporation.

3. A process for the production of (+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-l of formula(+)-l which comprises treatment of i-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-l of formula(i)-l F HN 1-1 dissolved in acetone with one mole ofD-()-0,0-dibenzoyltartaric acid hydrate dissolved in acetone, separationof ()-3r-N-monomethylamino- 4c-phenyl-4t-ethoxycarbonylcyclohexenelD-()-0,0-dibenzoyltartrate by filtration and isolation of the product bybasification, extraction and evaporation. I

4. A process for the production of the hydrochloride salt of(+)-3r-N-monomethylamino-4c-phenyl-4tethoxycarbonylcyclohexene-l whichcomprises treatment of(+)-3r-N-monomethylamino-4c-phenyl-4tethoxycarbonylcyclohexene-l with asolution of hydrogen chloride and ethyl acetate.

5. A process for the production of (+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-lL-(+)-0,0-dibenzoyltartrate which comprises treatment of(:t)-3r-N-m0nomethylamino-4cphenyl-4t-ethoxycarbonylcyclohexene-1,dissolved in acetone with one mole of L-(+)-0,0-dibenzoyltartaric acidmonohydrate dissolved in acetone and isolation of the product byfiltration.

6. A process for the production of (+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-lD-()0,0-dibenzoyltartrate which comprises treatment of an acetonesolution of (+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-l with an acetonesolution D-()-0,0-dibenzoyltartaric acid monohydrate.

1. A COMPOUND OF FORMULA (+)-I
 2. A process for the production of(+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-1 offormula (+)-I
 3. A process for the production of(+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-1 offormula (+)-I
 4. A process for the production of the hydrochloride saltof (+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-1which comprises treatment of(+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-1 with asolution of hydrogen chloride and ethyl acetate.
 5. A process for theproduction of(+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-1L-(+)-O,O-dibenzoyltartrate which comprises treatment of ( + or -)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-1,dissolved in acetone with one mole of L-(+)-O,O-dibenzoyltartaric acidmonohydrate dissolved in acetone and isolation of the product byfiltration.
 6. A process for the production of(+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-1D-(-)-O,O-dibenzoyltartrate which comprises treatment of an acetonesolution of(+)-3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonylcyclohexene-1 withan acetone solution of D-(-)-O,O-dibenzoyltartaric acid monohydrate.